Myofilament Alterations Associated with Human R14del-Phospholamban Cardiomyopathy.

Phospholamban () is a major regulator of cardiac contractility, and human mutations in this gene give rise to inherited cardiomyopathies. The deletion of Arginine 14 is the most-prevalent cardiomyopathy-related mutation, and it has been linked to arrhythmogenesis and early death. Studies in -humanized mutant mice indicated an increased propensity to arrhythmias, but the underlying cellular mechanisms associated with R14del- cardiac dysfunction in the absence of any apparent structural remodeling remain unclear. The present study addressed the specific role of myofilaments in the setting of R14del- and the long-term effects of R14del- in the heart. Maximal force was depressed in skinned cardiomyocytes from both left and right ventricles, but this effect was more pronounced in the right ventricle of R14del- mice. In addition, the Ca sensitivity of myofilaments was increased in both ventricles of mutant mice. However, the depressive effects of R14del- on contractile parameters could be reversed with the positive inotropic drug omecamtiv mecarbil, a myosin activator. At 12 months of age, corresponding to the mean symptomatic age of R14del- patients, contractile parameters and Ca transients were significantly depressed in the right ventricular R14del- cardiomyocytes. Echocardiography did not reveal any alterations in cardiac function or remodeling, although histological and electron microscopy analyses indicated subtle alterations in mutant hearts. These findings suggest that both aberrant myocyte calcium cycling and aberrant contractility remain specific to the right ventricle in the long term. In addition, altered myofilament activity is an early characteristic of R14del- mutant hearts and the positive inotropic drug omecamtiv mecarbil may be beneficial in treating R14del- cardiomyopathy.